DESCRIPTION: (Applicant's Abstract) In spite of the significant advances made in early diagnosis and treatment of cancer, the majority of solid tumors are still incurable with the treatments currently available. Several immune-enhancing strategies have been therefore developed in experimental models, and although they have been very successful in "protecting" against a subsequent tumor challenge, they have often failed when given shortly after the solid tumor is established. Recently, utilizing T cell receptor (TCR) transgenic mice specific for a model tumor antigen expressed on a Renal cell carcinoma (RencaHA), we have found that antigen specific CD4+ T cells are rendered anergic early during tumor progression. The induction of T cell unresponsiveness occurs in the absence of tumor invasion to the lymphoid organs, suggesting mechanism(s) that are independent of a direct tumor-CD4+ T cell interaction, Indeed, using parent-into-Fl bone marrow chimeras we have unambiguously demonstrated that tumor antigen processing and presentation by bone marrow derived antigen-presenting cells (APCs) is the dominant mechanism underlying the development of tumor antigen specific T cell tolerance ("cross-tolerance"). Importantly, the induction of this state of T-cell unresponsiveness is associated with the loss of therapeutic tumor-cell based vaccine efficacy pointing therefore, to tumor induced antigen-specific T-cell tolerance as a critical barrier in the design of an effective cancer immunotherapy. Therefore, the overall goal of this proposal is to utilize this model of solid tumor-induced tolerance for elucidating the mechanism(s) at the APC level that are central in the decision leading to activation versus tolerance of antigen-specific T cells. Furthermore, we will determine whether decreasing the tumor burden (by surgery and/or radiation treatment) may result in reversal -or not- of tumor-induced tolerance. Most importantly - in terms of clinical relevance - we will explore whether immunotherapeutic strategies aimed to enhance APCs function (treatment with CD4O activating antibodies) and/or strategies aimed to enhance T cell function (blocking T-cell inhibitory signals with anti-CTLA4 blocking antibodies) may break this state of T cell unresponsiveness. The knowledge to be gained in this endeavor will shed light not only on the basic biology of host-tumor interaction, but it will provide us with the therapeutic tools needed for safely break solid tumors-induced tolerance, and achieving the long-elusive success of cancer immunotherapy.